The present invention relates generally to introducing therapeutic or tracer agents into selected cells and trapping the agents within the cells to optimize therapeutic activity or tracer detectability.
In many disease states, most obviously in various forms of cancer, it is desirable to target therapeutic and/or tracer agents to specific cell types. Two problems exist in such targeting. The first is to cause specific uptake of the radioisotope or other agent by the target cells. The second is to prevent the redistribution of the agent to other cells after uptake by the target cells to thereby optimize action of the agent.
Progress has been made on the first problem by attaching therapeutic or tracer agents to targeted proteins, e.g. monoclonal antibodies, glycoproteins which are targeted to specific cell receptors recognizing certain terminal carbohydrate moieties, etc. In each case, the targeted protein and attached therapeutic or tracer agent are incorporated into the target cell after binding to specific membrane elements.
Some progress has also been made regarding the second problem relating to the trapping of therapeutic or tracer agents once they are incorporated into the target cells.
For example, one approach to the problem of intracellular trapping arose from the long time use of a common disaccharide, sucrose, as a marker of fluid endocytosis. Once incorporated into cells by fluid endocytosis, sucrose is not metabolized since mammalian cells lack the necessary glycosidase. The sucrose is therefore effectively trapped within the cell since the sucrose is unable to cross cell membranes. The sucrose thus accumulates over time as a cummulative measure of fluid uptake. Taking advantage of these properties of sucrose, a technique was developed for determining the sites of degradation of plasma proteins by covalently attaching radiosucrose to the particular protein to be introduced into a cell for degradation (Pittman and Steinberg, 1978, Biochem. Biophys. Res. Commun. 81, 1254-1259; Pittman et al, 1979, J. Biol. Chem. 254, 6876-6879: Pittman et al, 1979, Proc. Natl. Acad. Sci. USA 76, 5345-5349). After injection of the tracer protein labeled with radiosucrose, the protein is degraded within the cells. The radiosucrose moiety is not degraded but remains trapped within those cells participating in uptake as a cummulative measure of degradation by those cells.
Although the above sucrose-based process has shown promise, it is limited to trapping only radiolabeled sucrose within the targeted cell. Since the .sup.14 C and .sup.3 H iostopes of sucrose are the only isotopes which are readily avilable, the method is limited in the possible radioisotopes of sucrose which can be introduced into cells as either therapeutic or tracer agents. Further, the adaptability of sucrose to carry separate therapeutic agents has not been demonstrated. There is therefore still presently a need to provide a method and trapping agent which is capable of trapping a wide variety of therapeutic and/or tracer agents within cells.